Revisiting the TCA cycle: Signaling to tumor formation

Trends in Molecular Medicine

Volumn 17, Issue 11, 2011, Pages 641-649

  Raimundo, Nuno ^a   Baysal, Bora E ^a   Shadel, Gerald S ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FUMARATE HYDRATASE; ISOCITRATE DEHYDROGENASE; SUCCINATE DEHYDROGENASE;

CARCINOGENESIS; CELL DIFFERENTIATION; CITRIC ACID CYCLE; GENE MUTATION; HUMAN; HYPOXIA; MITOCHONDRION; NONHUMAN; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; CELL DIFFERENTIATION; CELL HYPOXIA; CELL TRANSFORMATION, NEOPLASTIC; CITRIC ACID CYCLE; FUMARATE HYDRATASE; HUMANS; ISOCITRATE DEHYDROGENASE; MITOCHONDRIA; NEOPLASMS; SUCCINATE DEHYDROGENASE;

EID: 80054959409     PISSN: 14714914     EISSN: 1471499X     Source Type: Journal    
DOI: 10.1016/j.molmed.2011.06.001     Document Type: Review

References (69)

1. Scheffler I.E. Mitochondria 2008, John Wiley & Sons, Inc. 2nd edn.
2. Wallace D.C., et al. Mitochondrial energetics and therapeutics. Annu. Rev. Pathol. 2010, 5:297-348.
3. Holme E., et al. Multiple symmetric lipomas with high levels of mtDNA with the tRNA(Lys) A→G(8344) mutation as the only manifestation of disease in a carrier of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome. Am. J. Hum. Genet. 1993, 52:551-556.
4. Ishikawa K., Hayashi J. A novel function of mtDNA: its involvement in metastasis. Ann. N. Y. Acad. Sci. 2010, 1201:40-43.
5. Baysal B.E., et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000, 287:848-851.
6. Tomlinson I.P., et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat. Genet. 2002, 30:406-410.
7. Yan H., et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 2009, 360:765-773.
8. Dang L., et al. IDH mutations in glioma and acute myeloid leukemia. Trends Mol. Med. 2010, 16:387-397.
9. Dang L., et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009, 462:739-744.
10. Ward P.S., et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010, 17:225-234.
11. Kranendijk M., et al. IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 2010, 330:336.
12. Reitman Z.J., et al. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proc. Natl. Acad. Sci. U.S.A. 2011, 108:3270-3275.
13. Hao H.X., et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 2009, 325:1139-1142.
14. Niemann S., Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat. Genet. 2000, 26:268-270.
15. Astuti D., et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am. J. Hum. Genet. 2001, 69:49-54.
16. Baysal B.E., et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J. Med. Genet. 2002, 39:178-183.
17. Burnichon N., et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum. Mol. Genet. 2010, 19:3011-3020.
18. Vanharanta S., et al. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am. J. Hum. Genet. 2004, 74:153-159.
19. Baysal B.E. A recurrent stop-codon mutation in succinate dehydrogenase subunit B gene in normal peripheral blood and childhood T-cell acute leukemia. PLoS ONE 2007, 2:e436.
20. Stratakis C.A., Carney J.A. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J. Intern. Med. 2009, 266:43-52.
21. Gottlieb E., Tomlinson I.P. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat. Rev. Cancer 2005, 5:857-866.
22. Bayley J.P., et al. The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency. BMC Med. Genet. 2008, 9:20.
23. Alam N.A., et al. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum. Mol. Genet. 2003, 12:1241-1252.
24. Refae M.A., et al. Hereditary leiomyomatosis and renal cell cancer: an unusual and aggressive form of hereditary renal carcinoma. Nat. Clin. Pract. Oncol. 2007, 4:256-261.
25. Merino M.J., et al. The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am. J. Surg. Pathol. 2007, 31:1578-1585.
26. Lehtonen H.J., et al. Conventional renal cancer in a patient with fumarate hydratase mutation. Hum. Pathol. 2007, 38:793-796.
27. Toro J.R., et al. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am. J. Hum. Genet. 2003, 73:95-106.
28. Kiuru M., Launonen V. Hereditary leiomyomatosis and renal cell cancer (HLRCC). Curr. Mol. Med. 2004, 4:869-875.
29. Lehtonen H.J. Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics. Fam. Cancer 2011, 10:397-411.
30. Raimundo N., et al. Differential metabolic consequences of fumarate hydratase and respiratory chain defects. Biochim. Biophys. Acta 2008, 1782:287-294.
31. O'Flaherty L., et al. Dysregulation of hypoxia pathways in fumarate hydratase-deficient cells is independent of defective mitochondrial metabolism. Hum. Mol. Genet. 2010, 19:3844-3851.
32. Yogev O., et al. Fumarase: a mitochondrial metabolic enzyme and a cytosolic/nuclear component of the DNA damage response. PLoS Biol. 2010, 8:e1000328.
33. Majmundar A.J., et al. Hypoxia-inducible factors and the response to hypoxic stress. Mol. Cell 2010, 40:294-309.
34. Dalgard C.L., et al. Endogenous 2-oxoacids differentially regulate expression of oxygen sensors. Biochem. J. 2004, 380:419-424.
35. Isaacs J.S., et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 2005, 8:143-153.
36. Koivunen P., et al. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J. Biol. Chem. 2007, 282:4524-4532.
37. Selak M.A., et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 2005, 7:77-85.
38. Ottolenghi C., et al. Clinical and biochemical heterogeneity associated with fumarase deficiency. Hum. Mutat. 2011, 10.1002/humu.21534.
39. Hewitson K.S., et al. Structural and mechanistic studies on the inhibition of the hypoxia-inducible transcription factor hydroxylases by tricarboxylic acid cycle intermediates. J. Biol. Chem. 2007, 282:3293-3301.
40. Lu H., et al. Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J. Biol. Chem. 2005, 280:41928-41939.
41. Lu H., et al. Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J. Biol. Chem. 2002, 277:23111-23115.
42. Vander Heiden M.G., et al. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009, 324:1029-1033.
43. Ozer A., Bruick R.K. Non-heme dioxygenases: cellular sensors and regulators jelly rolled into one?. Nat. Chem. Biol. 2007, 3:144-153.
44. Pollard P.J., et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum. Mol. Genet. 2005, 14:2231-2239.
45. Pollard P., et al. Evidence of increased microvessel density and activation of the hypoxia pathway in tumours from the hereditary leiomyomatosis and renal cell cancer syndrome. J. Pathol. 2005, 205:41-49.
46. Vanharanta S., et al. Distinct expression profile in fumarate-hydratase-deficient uterine fibroids. Hum. Mol. Genet. 2006, 15:97-103.
47. Pollard P.J., et al. Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway. Cancer Cell 2007, 11:311-319.
48. Igarashi P., et al. Ksp-cadherin gene promoter. II. Kidney-specific activity in transgenic mice. Am. J. Physiol. 1999, 277:F599-F610.
49. Lehtonen R., et al. Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors. Am. J. Pathol. 2004, 164:17-22.
50. Kaelin W.G. The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma. Clin Cancer Res. 2007, 13:680s-684s.
51. Raimundo N., et al. Downregulation of SRF-FOS-JUNB pathway in fumarate hydratase deficiency and in uterine leiomyomas. Oncogene 2009, 28:1261-1273.
52. Braun T., Gautel M. Transcriptional mechanisms regulating skeletal muscle differentiation, growth and homeostasis. Nat. Rev. Mol. Cell Biol. 2011, 12:349-361.
53. Schafer F.Q., Buettner G.R. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic. Biol. Med. 2001, 30:1191-1212.
54. Hsieh J.Y., et al. Long-range interaction between the enzyme active site and a distant allosteric site in the human mitochondrial NAD(P)+-dependent malic enzyme. Arch. Biochem. Biophys. 2009, 487:19-27.
55. Zhang Z., et al. Identification of lysine succinylation as a new post-translational modification. Nat. Chem. Biol. 2011, 7:58-63.
56. Wellen K.E., et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 2009, 324:1076-1080.
57. Figueroa M.E., et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010, 18:553-567.
58. Xu W., et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 2011, 19:17-30.
59. Chowdhury R., et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011, 12:463-469.
60. Hartong D.T., et al. Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle. Nat. Genet. 2008, 40:1230-1234.
61. Odievre M.H., et al. A novel mutation in the dihydrolipoamide dehydrogenase E3 subunit gene (DLD) resulting in an atypical form of alpha-ketoglutarate dehydrogenase deficiency. Hum. Mutat. 2005, 25:323-324.
62. Rouzier C., et al. The severity of phenotype linked to SUCLG1 mutations could be correlated with residual amount of SUCLG1 protein. J. Med. Genet. 2010, 47:670-676.
63. Rustin P., et al. Succinate dehydrogenase and human diseases: new insights into a well-known enzyme. Eur. J. Hum. Genet. 2002, 10:289-291.
64. Pantaleo, M.A. et al. (2011) SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. J. Natl. Cancer Inst. (in press).
65. Fukao T., et al. Clinical and molecular characterization of five patients with succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency. Biochim. Biophys. Acta 2011, 1812:619-624.
66. Bourgeron T., et al. Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency. J. Clin. Invest. 1994, 93:2514-2518.
67. Greenberg D.A., et al. Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy. Am. J. Hum. Genet. 2005, 76:139-146.
68. Wise D.R., et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl. Acad. Sci. U.S.A. 2008, 105:18782-18787.
69. Zhao F., et al. Imatinib resistance associated with BCR-ABL upregulation is dependent on HIF-1alpha-induced metabolic reprogramming. Oncogene 2010, 29:2962-2972.